Design, synthesis and biological evaluation of novel benzothiadiazine derivatives as potent PI3Kδ-selective inhibitors for treating B-cell-mediated malignancies was written by Ma, Xiaodong;Wei, Jun;Wang, Chang;Gu, Dongyan;Hu, Yongzhou;Sheng, Rong. And the article was included in European Journal of Medicinal Chemistry in 2019.Category: nitriles-buliding-blocks This article mentions the following:
A series of 24 benzothiadiazine derivatives I (R1 = Ph, 4-F-Ph, 3-CF3-Ph, etc; R2 = H, F, Cl; R3 = Me, Et; R4 = H, F, Cl), II, III (R5 = Ph, 4-F-Ph, 4-OCF3-Ph, 3-Py; R6 = H, F) with structural novelty were designed, synthesized and biol. evaluated as PI3Kδ-selective inhibitors. Structure-activity relationship (SAR) study showed that, compounds I (R1 = Ph; R2 = Cl; R3 = Et; R4 = H) and II (R2 = Cl; R3 = Me) were identified with single-digit nanomolar IC50 values against PI3Kδ and submicromolar GI50 values against human malignant B-cell line SU-DHL-6. Furthermore, chiral resolution of the key amine intermediate of these two compounds was performed to achieve corresponding enantiomers. Compounds (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenyl-2Hbenzo[e][1,2,4]thiadiazine 1,1-dioxide(IC50: 4.6 nM) and (S)-4-amino-6-((1-(8-chloro-1,1-dioxido-2-phenyl-2H-benzo[e][1,2,4]thiadiazin-3-yl)ethyl)amino)pyrimidine-5-carbonitrile(IC50: below 0.32 nM) demonstrated comparable and superior PI3Kδ inhibitory activity, resp., to that of idelalisib. Addnl., both the compounds exerted enhanced anti-proliferative activity against the SU-DHL-6 cell line than that of idelalisib and they exhibited excellent PI3Kδ selectivity. The in vivo pharmacokinetic (PK) study revealed that (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenyl-2Hbenzo[e][1,2,4]thiadiazine 1,1-dioxide displayed good plasma exposure and an acceptable oral bioavailability of 29.2% and can further be developed as a potential therapeutic agent for battling B-cell-mediated malignancies. In the experiment, the researchers used many compounds, for example, 4-Amino-6-chloropyrimidine-5-carbonitrile (cas: 60025-09-4Category: nitriles-buliding-blocks).
4-Amino-6-chloropyrimidine-5-carbonitrile (cas: 60025-09-4) belongs to nitriles. Nitrile function is a very important functional group because it can be manipulated to other functional groups such as carboxylic acid by hydrolysis or amine by reduction, respectively. Asymmetric bioreduction of nitriles is an attractive route to produce optically active nitriles as current metal-catalyzed hydrogenations tend to have low reactivity.Category: nitriles-buliding-blocks
Referemce:
Nitrile – Wikipedia,
Nitriles – Chemistry LibreTexts